Amphotericin B (AmB) is a very effective antifungal agent, and resistance in clinical isolates is rare. However, clinical treatment with AmB is often associated with severe side effects. Reducing the administration dose of AmB by combining it with other agents is a promising strategy to minimize this toxicity. In this study, we screened a small compound library and observed that the anti-obesity drug rimonabant exhibited synergistic antifungal action with AmB against Candida species and Cryptococcus neoformans. Moreover, the combination of AmB and rimonabant exhibited synergistic or additive effects against Candida albicans biofilm formation and cell viability in preformed biofilms. The effects of this combination were further confirmed in vivo using a murine systemic infection model. Exploration of the mechanism of synergy revealed that rimonabant enhances the fungicidal activity of AmB by increasing cellular oxidative stress and cell membrane permeability. These findings provide a foundation for the possible development of AmB–rimonabant polytherapies for fungal infections.

中文翻译：

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利莫那班通过增加细胞氧化应激和细胞膜通透性来增强两性霉素 B 的抗真菌活性

两性霉素 B (AmB) 是一种非常有效的抗真菌剂，临床分离株的耐药性很少。然而，AmB 的临床治疗通常伴随着严重的副作用。通过将 AmB 与其他药物组合来减少 AmB 的给药剂量是一种有希望的策略，可以最大限度地减少这种毒性。在这项研究中，我们筛选了一个小型化合物库，并观察到抗肥胖药物利莫那班与 AmB 对念珠菌属和新型隐球菌具有协同抗真菌作用。此外，AmB 和 rimonabant 的组合对白色念珠菌生物膜的形成和预制生物膜中的细胞活力表现出协同或相加作用。使用鼠全身感染模型在体内进一步证实了这种组合的效果。对协同作用机制的探索表明，利莫那班通过增加细胞氧化应激和细胞膜通透性来增强 AmB 的杀菌活性。这些发现为可能开发用于真菌感染的 AmB-利莫那班联合疗法奠定了基础。